Tethered prodrugs

Abstract

Compounds wherein a biologically active molecule is coupled to a glutathione analog through a conjugated system which permits activation of the biologically active molecule while retaining the biologically active molecule tethered to the glutathione analog are useful as tethered prodrugs that slow the rate of clearance of an active biomolecule through the multidrug resistance pump.

We claim: 
     
       1. A compound of the formula ##STR14## and the amides, esters, mixed ester/amides and salts thereof, wherein: S x  is S═O, O═S═O, S═NH, HN═S═O, Se═O, O═Se═O, Se═NH, HN═Se═O, S +  R' wherein R' is alkyl (1-6C), or O--C═O or HN--C═O; YCO is selected from the group consisting of γ-Gly, β-Asp, Glu, Asp, γ-GluGly, β-AspGly, GluGly and AspGly;   AA C  is an amino acid linked through a peptide bond to the remainder of said compound of formula (1);   each R is independently H or a noninterfering substituent;   (conj) is a conjugated system;   m is 0 or 1;   n is an integer of 1-4;   each of X 1  and X 2  is independently S, O, or NH; and   Z is a moiety which, when associated with P(O)X 1  X 2 , results in a biologically active moiety which biologically active moiety is a tethered phosphoramide mustard or a tethered phosphorodiamidate mustard;   and wherein each of the dotted lines represents a covalent bond between (CR 2 ) n  and C*, C + , or a carbon in the conjugated system if present with the proviso that one and only one said bond is present.   
     
     
       2. The compound of claim 1 wherein m=0; and/or wherein YCO is γ-glutamic acid; and/or   wherein AA C  is alanine, phenylalanine, glycine or phenylglycine; and/or   wherein each R is independently H, lower alkyl (1-4C) or phenyl; and/or   wherein Z is N(CH 2  CH 3 ) 2 , N(CH 2  CH 2  Cl) 2 , NHCH 2  CH 2  Cl, N(CH 2  CH 2  Br) 2 , or NHCH 2  CH 2  Br; and/or   wherein S x  is O═S═O.   
     
     
       3. The compound of claim 2 wherein each R is H. 
     
     
       4. The compound of claim 2 wherein AA C  is phenylglycine. 
     
     
       5. The compound of claim 2 which has the formula ##STR15## wherein YCO is γGlu and AA C  is phenylglycine, glycine, or β-alanine, and Z is N(CH 2  CH 2  Cl) 2  or NHCH 2  CH 2  Cl. 
     
     
       6. A compound for the preparation of the compound of claim 4 of the formula selected from the group consisting of: ##STR16## and the amides, esters, mixed ester/amides or salts thereof, wherein: S* is S +  or S x  ; S +  is S or Se;   S x  is S═O, O═S═O, S═NH, HN═S═O, Se═O, O═Se═O, Se═NH, HN═Se═O, S +  R' wherein R' is alkyl (1-6C), or S x  is --O--C═O or --HN--C═O;   Y is selected from the group consisting of γ-Glu, β-Asp, Glu, Asp, γ-GluGly, β-AspGly, GluGly and AspGly;   AA C  is an amino acid linked through a peptide bond to the remainder of said compound of formula (1);   each R is independently H or a noninterfering substituent;   m is 0 or 1;   n is an integer of 0-4;   each of X 1  and X 2  is independently S, O, or NR' wherein R' is H or a noninterfering substituent; and   Z is a moiety which, when associated with P(O)X 1  X 2 , results in a biologically active moiety, which biologically active moiety is a tethered phosphoramide mustard or a tethered phosphorodiamidate mustard.